Glutaricaciduria I

Synonyms of Glutaricaciduria I

Dicarboxylic Aminoaciduria

GA I

Glutaricacidemia I

Glutaric Acidemia I

Glutaric Aciduria I

Glutaryl-CoA Dehydrogenase Deficiency

Glutaurate-Aspartate Transport Defect

General Discussion

Glutaricaciduria I (GA-I) is a rare hereditary metabolic disorder, caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. One of a group of disorders known as "organic acidemias," it is characterized by an enlarged head (macrocephaly), decreased muscle tone (hypotonia), vomiting, and excess acid in the blood. Affected individuals may also have involuntary movements of the trunk and limbs (dystonia or athetosis) and mental retardation may also occur.

Babies with glutaricaciduria I are sometimes mistakenly thought by medical professionals to be abused babies because they present with subdural and/or retinal hemorrhages.

Signs & Symptoms

Babies with glutaricaciduria I usually appear normal at birth. At almost any time during the first year of life, usually as a result of an acute illness, there may occur a crisis involving decreased muscle tone (hypotonia), vomiting, and high levels of organic acids in the blood, and central nervous system degeneration. Such babies often assume strange positions due to disordered muscle tone (dystonia), and involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs may also occur. Mental retardation may accompany these symptoms.

Elevated concentrations of glutaric acid, beta-hydroxy-glutaric acid and occasionally glutaconic acid appear in the urine of children with this disorder. Excretion of glutaric acid in the urine may exceed 1 gram per day, an excessive amount. Glutaric acid concentrations are also elevated in blood serum, cerebrospinal fluid, and body tissues. Some of these patients may have unusual facial features (dysmorphia). A type of spasm in which the head and the heels are bent backward while the trunk is bowed forward (opisthotonus) may also occur.

Causes

Glutaricaciduria is an autosomal recessive hereditary disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. Accumulation of 5- carbon dicarboxylic acids may impair synthesis of gamma-aminobutyric acid (GABA), which functions as a neurotransmitter in the brain, inhibiting nerve excitation. The gene associated with glutaricaciduria I has been mapped to chromosome 19 (19p13.2).

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 19p13.2″ refers to band 13 on the short arm of chromosome 19. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Glutaricaciduria is a very rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 cases of this type of organic aciduria in the United States.

Related Disorders

There are many rare disorders caused by enzyme deficiencies. To locate these disorders in the Rare Disease Database choose “Enzyme Deficiency” as your search term.

There are two forms of glutaricaciduria II which occur during different stages of life. They are both forms of organic acidemias which are a group of metabolic disorders characterized by excess acid in the blood and urine.

1) Glutaricaciduria IIA (GA IIA), neonatal form of glutaricaciduria II. This neonatal form of glutaricaciduria II is a very rare, sex-linked hereditary disorder characterized by large amounts of glutaric and other acids in blood and urine. Some researchers believe the disorder is caused by a defect in the breakdown of acyl-CoA compounds.

2) Glutaricaciduria IIB (GA IIB; Ethylmalonic Adipicaciduria), adult form of glutaricaciduria II. This milder form of the disorder is inherited as an autosomal recessive trait. Acidity of the body tissues (metabolic acidosis), and a low blood sugar level (hypoglycemia) without an elevated level of ketones in body tissues (ketosis), occur during adulthood. Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme “multiple acyl-CoA dehydrogenase”. (For more information on this disorder, choose “Glutaricaciduria II” as your search term in the Rare Disease Database.)

Diagnosis

Glutaricaciduria is suspected upon a finding of excessive urinary glutaric acid and confirmed by measuring the presence and concentration of the deficient enzyme in white blood cells (leukocytes). Detection of the disorder in a fetus may be possible by testing for the enzyme glutaryl CoA dehydrogenase. It is important to test for this disorder as soon after birth as possible.

Standard Therapies

Treatment

Acute episodes of acidity in blood and body tissues (acidosis) and dehydration are treated with fluids and bicarbonate. Peritoneal dialysis hemodialysis may be necessary. The usefulness of restricting the amino acids lysine, hydroxylysine, and tryptophan (which generate glutaric acid when they are metabolized), is not established at the present time. Many of the adverse effects of organic acidemias are due to secondary carnitine depletion. Such patients should have plasma carnitine measured and, if deficient, begin a supplement of 100-300 mg/kg/day of oral l-carnitine.

Genetic counseling is recommended for families of children with glutaricaciduria.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

NORD's Rare Disease Database provides brief introductions for patients and their families to more than 1,200 rare diseases. This is not a comprehensive database since there are nearly 7,000 diseases considered rare in the U.S. We add new topics as we are able to do so, with the help of rare disease medical experts.

If you are seeking information about a rare disease that is not in this database, we would suggest contacting the Genetic and Rare Diseases Information Center (GARD) at the National Institutes of Health. NIH has the most complete database of rare diseases in the U.S.

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